Process of preparing arseno compounds which are stable in solution



Patented Wiley 8, 1923.

warren stares WILHELHT KOLLE, OF FRANKFORT-ON-THE-MAIN, GERMANY, ASSIGN'OR TO BARB- WERKE TOR/M. MEISTER LUCIUS & BE'll'NING, OF HOCHST-ON-THE-Mm, GER- MANY, A. CORPQRATION F GERMANY.

PROCESS OF PREPARING ARSENO COMPOUNDS WHICH ARE STABLE IN SOLUTION.

1% Drawing.

To all whom it may concern:

Be it known that I, VILHELM KoLLE, a citizen of Germany, residing at Frankforton-thedvlain, Germany, have invented cer- 5 tain new and useful Improvements in a Process of Preparing Arseno Compounds Which Are Stable in Solution, of which the following is a specification.

I have found that by combining arsenobenzene derivatives, including the sulphoxylate compounds, with sulphoxylate-compounds of such amino-bodies as are not arsenobenzene derivatives stable arseno-compounds are obtained. In working out this invention I have made the remarkable observation that by combining such sulphoxylate compounds, as for instance those of the aminophenols and their alkylethers there are obtained particularly new biological effects. The biological modification consists in that the dosis tolerate. of the mixture is considerably larger,-and consequently its toxicity by far less as should be calculated according-to the dosis tolerate, of the 2 components, withoutits therapeutical value being thereby materially reduced. Thus there has been found that when combining the sulphoxylate of 1 phenylp arsenobenzene-5-pyrazolone-QB-dimethyli-iminom'ethylene with the'sulphoxylate of p-oxy-pheny eneiminomethylene (see Exam-.

ple 1), there was obtained as the tolerable dose not, as it should have been presumed, the average value of the respective dose of the components, but a dosis tolerata which was four times as large. Furthermore the surprising fact has been ascertained that in spite of the admixture of the sulphoxylate compounds free from arsenic, which have no action upon spirochaetee, the approximately absolute quantity by weight necessary for the healing of one kilo of the animals weight, remained nevertheless the same, while the therapeutical etl'ect, calculated on the amount of arsenic, had increased four times as much. Of fundamental importance as a proof for realization of new unexpected chemotherapeutical effects by means of the above described preparaing arsenobenzene derivatives which have almost no action at all upon trypanosomae tions, is also the fact that when combin- Application filed January 12, 1922. Serial no. 528,836.

such as the sulphyoxylate of 1-phenyl-p-arsenobenzene-5-pyramlone-2.3-dimethyliminomethylene with a solution of the sulphoxylate of p oxyphenyleneiminomethylene which has also no action upon trypanosomae, the compounds thus'obtained act upon trypanosomee with a chemotherapeutical index of 1 3. The combination of the compounds may be effected either by mixing them in a dry state or by combining solutions or suspensions therefrom with each other and then, if it is not preferred to use the solution thus obtained, removing the dissolving or suspending agent by evaporation.

Compounds of sulphoxylate of amino bodies may be obtained by briefly heating the aminocompound to 7080 for instance o-aminophenol or urea with sodium formaldehydesulphoxylate (see Reinking, Dehnel und Labhardt. Ber. d. deutsch. chem. Ges. 38, 10691905.Binz und Marx, Ber. 43,2344 1910) These compounds are easily soluble in water and unstable in air and they decolorize by reduction a solution of indigo carmin. With an iodine solution they may be titrated using four mol. of iodine on 1 mol. of sulphoxylate.

Ewo/mples'.

ponent tol. =5; and for the other component tol.=%= and being grams figures. In

this case a. tol.:1; b. tol.=1, consequently (a,+ b) tol. =2 and tol'. thedosis tolerata of the mixture being expressed in grams. Thus the theoretical figure is toL:

however been found by tests on animals tol.:l/4O g, that ing tabular statement, the last but one column containing the values for the dosis is to say a considerable diminution of toX- tolerata in each case, as it is calculated from lclty. I the formula stated, the last column the 5 Further examples are given in the followvalues found by the tests on animals.

Mixture of the Ex components.

' Arseno com onnds. T01. Components free from arsenic. Tol.

amPlep T01. T01.

calcul. found.

2 lccm.oia 10%solution oftheearbaim'nate i4-arsenodil/250 1 com. p amino henolmethylene- 1/200 1/250 l/ l-phen i 2.3-dimethyl-4-amino-5-gyrazolone and 1 sulphoxylate oil strength. com. o a solution of bismethy -amino-tetraminoarseno-benzene'cai'baminate. O H

N .omosona.

3. 1 g. ofhydrochlorideof t-ersenodi-lhen12.3-dim ethyll/250 l g.%eminohenol with g. oiiormal- 1/200 1/225 1/100 4-amino-5-pyrazolone precipitat wit a solution of 1/300 de yde sucphoxylate Na condensed 1/150 sodium carbonate. into 110- H -NH-CH.O.SON3.

4 2 com. 018 5% solution ofbismethylamino-tetraamino 1/300 0.5 com, p-amino-phenolmethylene 1/200 mm mm arseno-benzenecai'baminate. sulphoxylate of 10% strength. 1/270 1/175 5 lg.oihydrochlorideoi4-arsenodi-l-phenyl-2.3dirnethyi- 1/250 1 g. o-amino henoie with 1 g. iormal- 1/200 1/225 0 4-ammo-5-py'razoione precipitated with a solution of dehyde'su phoxylste Na condensed 1 75 sodium carbonate. into q on / NH.cH,0soNa.

6. 0.5 com. or a 10% solution of the catbaminate of 4'-arse- 1/25{) 0.5 ccm. oemino-phenol-methylene 1/200 1/130 1 0 nodi-l-phenyl, 2.3-dlI11Bthy'l-44mlfl0 5-pyrazolone and 1/10 snlphoxylate of 10% strength. 0.5 ccm. of 2.10% solution of the sulphoxylate of the same compound.

7. 2 com. 4.4-dimethyiamlno-3.3 5.5-tetraaminoerseno- 1300 lccm. nisidinemeth lenesul hox 1 4 benzenecarbaminate of 5% strength. I mt 330% Strength, y p y [75 1/187 1/ 100 OEiHz NBLCHmOSONa.

8. 2 com. 4.4'-dimethyl-amino-3.3 5.5-tetraaminoarseno- 1300 1 cem.o-anisidin-meth lenesul hox 1 benzene carbeminate or 5% stiength. 7 late 0! 10% strength. y p y /25 11162 1,100

OCHa NH.CHZOSONa.

9. 10cm. 01 4'-arsenodl-lhenyl-2.3-dimethy-p azolon- 1100 lccm. heneti-din-meth lcne-sul h- 1100 100 iminomethylenesulp oxylate of 10% strengt l oxylgtgof 10% strength. p 1/ 1,60

zHs

I nncmosona.

10. 2ccm.of a 10% solution of the carbaminate of l-arsenodil/250 0.5 0cm. etii laminometh lene sul h- 1 5 l 215 l I l-phenyl 2.3-dimetl1yl-i-amino-5-pyrazolone. oxyme A strength? P l 15 11. Like Example 10 l/250 0.5 0cm. ureamethylensulphoxylate of l/ 1/205 1/00 10% strength.

Other biological experiments not stated above show'that in spite of this diminution of toxicity the therapeutical value has remained almost unaltered, but that above all the chemotherapeutieal index has unexpectedly increased. Our invention therefore, :onstitutes anew and surprising achievement which could not be obtained by any of the hitherto known chemotherapeutical processes.

From these biological results may be coneluded that. there have been formed new chemical compounds from the arsenobenzene' derivatives and the above described sulphoxylate derivatives. The probability of this conclusion is strengthened by the fact that it is possible by adding the sulphoxylates to arsenobenzene derivatives which are insoluble in water tor instance 4.4 -dioxy-3.3 -diaminoarsenobenzene and 4 arsenodi-1-phenyl-2.3-dimethyl 4 amino- 5- pyraz-olone-4 to render them soluble in water, as will be seen from the following examples.

12. 1 g. of p-aminophenol is subjected to condensation at -80 C. with 3 g. of formaldeh'ydesulphoxylate in 3 com. of water. The resulting mass is diluted with water to 10 com. and there is added 1 g. of sodium sal. of 4.4 -dioXy-3B diaminoarsenobenzene dissolved inlO com. of water. The precipitate thus obtained is dissolved with about 20 drops of caustic soda solution.

If carbon dioxide is then introduced no dioxydiaminoarsenobenzene is precipitated, a fact from which may be concluded that the base employed has entered into a new watersoluble compound.

13. 1 g. of the silver compound of 4.4 dioxy 3.3 diaminoarsenobenzene (British PatentNo. 24,420/12) dissolved in 5 ccm. of water is precipitated by introducing carbondioxide. The precipitate dissolves in the course of about a hour with a slight alkaline reaction after adding the condensation product of 1 g. o-aminophenol and 1 g. of formaldehydesulphoxylate in 5.5 ccm. of water. 7

14. 5 g. of the silver compound mentioned in Example 12 dissolved in 25 ccm.'of water are precipitated by introducing carbon dioxide. The precipitate dissolves in the course of about hour after adding the condensation roduct of 5 gr. of p-aminophenol an 5 g. of formaldehyde sulphoxylate in 25 com. of water.

15. 2 g. of hydrochloride of 4-arsenodi-1- phenyl 2.3-dimethyL 1-amino 5 pyrazolone dissolved in 2 com. of water are mixed with 3 com. of caustic soda solution. To the base thus precipitated and suspended, there is added a solution of sulphoxylate of pox phenylene-imino-methylene HQC IL. N .CH OSONa produced by warming for a short time in the water bath 1 gr. of paminophenol with 1 g. of formaldehydesulphoxylate in 1.5 com. of water, adding 2 com. of caustic soda solution, filling up with water to 20 com. and filtering. The 4-arsenodi-1-phenyl-2.3-dimethyl'- 4i amino- S-pyrazolone dissolves immediately.

16. 2 g. of hydrochloride of 4J-arsenodi- 1-phenyl-2.3-dimethyl 4-amino-5-pyrazolone dissolved in 2 com. of water and precipitated by adding 3 com. of g caustic soda solution are mixed with a solution of sulphoxylate of o-oxyphenyleneiminomethylene produced by warming for a short time 1 g. of o-aminophenol with l g. of formaldehydesulphoxy late in 1.5 com-of water, adding 2 com. of gcaustic soda solution, filling up precipitated by adding 1.5 com. of caustic soda solution are mixed with 1. g. of anthranilido methylene sulphoxylate dissolved in 2 com. of water and 2 com. of

The product dissolves on being stirred for a short time.

Claims: 1. The process of making arseno preparations which are stable in solution, which 2 v E caustic soda solutlon.

comprises combinin arseno-benzene derivatives with sulphoxy ate compounds of such amino bodies as are not arsenobenzene derivatives.

2. The process of making arseno preparations which are stable in solution by combining arsenobenzene derivatives with sulphoxylate compounds of such amino bodies as are not arsenobenzene derivatives, which comprises mixin said arsenobenzene de-' rivatives with said amino bodies.-

3. Process of making a'rseno preparations which are stable in solution, which comprises combining arsenobenzene derivatives with sulphoxylate compounds of such amino bodies as are not arsenobenzene derivatives in solution.

4. Process of making arseno preparations which are stable in solution, which comprises mixing solutions of arsenobenzene derivatives with solutions oi sulphoxylate compounds of such amino bodies as are not arsenobenzene derivatives.

5. Process of making arseno preparations which are stable in solution, which comprises, combining arsenobenzene derivatives with sulphoxylate compounds of such amino bodies as are not arsenobenzene derivatives in solution, and isolating the solid product from the dissolving agent.

6. As new products, the bodies obtainable by combining arsenobenzenes With sulphoxylate compounds of such amines as are not arsenobenzenes, said bodies being readily soluble in Water, more stable in solution than their components, their dosis tolerata being considerably larger than the calculated dosis tolerata of the components, and their therapeutical value being substantially as reat as the therapeutical value of the arseno enzene component.

7 As new products, the bodies obtainable by combining arsenobenzenes with sulphoxylate compounds of such aminophenols as are not arsenobenzenes, said bodies being readily soluble in Water, more stable in solution than their components, their dosis tolerata being considerably larger and their toxicity considerably less than the calculated dosis tolerata of the components,.and their therapeutical value being substantially undiminished.

8. As new roducts, arsenobenzenes combined with su phoxylate compounds of such amino bodies as are not a'rsenobenzenes.

In testimony whereof, I affix my signatnre.

WILHELM KOLLE. 

